2. herpes zoster- origins Herpes Zoster “Shingles” A one sided and widespread skin disease Ganglionic latency (like HSV-1? No….) Immune Resolution Adult-Child contact Replication in Tonsilar epith T cell mediated Viremia to skin Latent for decades… Then reactivation Chickenpox Neurons Support cells

3. Risk Factors for zoster Risk Factors for zoster Age - most zoster occurs in those over 50 Cellular immune status – AIDS – Radiation Therapy – Cancer (esp. lymphoma) – Immunosuppresion from medical therapies BMT & Transplants (30-55% in a year!) Evidence suggests CD4 >> CD8 are critical to control of VZV latency

4. Herpes Zoster -signs Pain – Before, during and after Vesicular skin lesions Lesions do not cross the midline of the face -come from ganglia Many lesions over wide area- -viral replication in the ganglia -many neurons deliver virus to skin Fever & Depression. Tic (“tic deleroux”)

5. Ocular Problems of zoster VZV can potentially infect every ocular tissue !! Punctate epithelial keratitis (PEK) Dendritic keratitis – w/o terminal bulbi Stromal inflammation – Harder to treat than HSV-1! Neurotrophic keratitis – Total loss of sensation – ulceration Rarer Findings Uveitis, retinitis, Acute retinal necrosis.

6. Neurotrophic Keratopathy The diabetic foot ulcer of the eye ~ 8% of HZO patients develop total loss of corneal sensation ~ 3% of HZO patients develop neurotrophic ulceration Iatrogenic insults are the main reason that neurotrophic corneas get into trouble.

7. Chronic Pain after zoster –Post Herpetic Neuralgia “Constant deep burning or aching” “Intermittent sharp,stabbing” Allodynia -pain invoked by light or innocuous stimulation, (e.g. clothing, wind gust)-may last long after removal - is the most distressing component of PHN -is the most common -is the most debilitating

8. To Brain: Conscious Perception of Pain Why does shingles cause pain? Spinothalamic Tract A  fibers C fibers Spinal cord Dorsal root ganglion SENSORY NERVES Latent VZV Reactivated VZV replicates in DRG….. Ouch!!! Yeow! ! -damages DRG, Induces Inflammation … Brain Signals To supress Nociception - interneurons Duh… -damages interneuron that blocks pain -changes  and C fiber physiology…… Chronic Pain!

9. Zoster Treatment 1. Treat the eye and active virus in skin 2. 3-5 + fold higher HSV-1 ACV dose needed for effect on VZV 3. Treat the post-herpetic pain -Tricyclic antidepressants (gabapentin) -Amitryptilline -Corticosteroids _Many PHN treatments don’t work -PHN is multifactorial syndrome Topical Acyclovir Oral Valacylcovir

10. Vaccination to prevent zoster –10 fold higher virus than varicella vaccine –VZV immune people get it! –Recommended to those over 60 –only human herpesvirus vaccine –Protection Results:- not everyone…… –51% drop in zoster –68% fall in burden of illness ( includes PHN)

11. Adenoviral Infections non-enveloped virus, 34Kbp DS-DNA, many viral proteins At least 51 identified Serotypes Two major ocular diseases Epidemic Keratoconjunctivitis (8 and 19) Pharyngoconjunctival fever (3,4, & 7)

12. EKC transferred by hands, instruments, solutions. Adenovirus can survive >35 days on a surface Epidemics arise from optometrists and ophthalmologists offices. Patients remain infectious for 14 days after onset of symptoms

13. Clinical Symptoms Foreign Body Sensation Tearing Photophobia Sore Throat Breathing Problems Conjuntivitis NO ANTIVIRAL YET Subeptielial inflitrates (immune mediated) may last long time -require steroids

14. Other Viruses causing Diseases of the Eye CMV (Fuchs? with HIV/AIDS Epstein Barr virus – Both common herpesviruses affecting most people Entero/coxsacivirus HIV (and everything resulting from it) Newcastle disease virus Vaccinia Mollocsum papilloma

15. Important Ophthalmic antivirals Triflourothymidine HSV-1>> VZV Acyclovir and valacyclovirHSV-1 and VZV Ganciclovir and valganciclovir CMV retinitis Foscarnet (phosphonformate)CMV (GCV r ) HSV,VZV Cidofovir CMV (GCVr ) HAARTHIV/AIDs

16. Acyclovir, gancyclovir and derivatives

17. l ACV Mechanism of Action –HSV VZV Thymidine (nucleoside) Kinase activates it –ACV TP binds Viral DNA polymerase >>>>> cell pol –Incorporated into DNA - acts as DNA chain terminator

18. Valacyclovir “Valtrex” Acyclovir Liver The ‘new’ oral versions - “valtrex” l ACV is degraded in stomach and not good orally l “Val” forms are Ester derivatives- higher oro-bioavailability –e.g. 63-72% stomach absorption vs 15% for ACV l drug is de-esterified by liver to give serum ACV l Allows high oral dosing (esp those needed for VZV) liver

19. ACV - Resistance Readily arises in culture – Defect /loss of TK in culture – DNA polymerase mutation altering affinity for ACV- ppp Rarely occurs in vivo – TK needed for reactivation and pathogensis of HSV,VZV – Occurs in AIDS due to long term treatments – Seems HSV VZV must make a ‘little” TK…..

20. Ganciclovir (Cytovene) Used for hCMV only– – CMV retinitis – organ transplants Now oral version -Val-GCV – Ester Protects in stomach Poor retinal/brain barriers crossing Use Ocular implants

21. l GCV Mechanism of action l similar to ACV- requires initial phosphorylation l DNA chain terminator –CMV has no TK gene!!! –CMV uses the UL97 viral protein kinase to phosphorylate GCV!! – Unlike ACV, GCV-PPP Inhibits both host and viral polymerase-toxic! GCV Resistance Arises frequently (longer treatments) 10% In Retinitis and organ transplants Change in polymerase, viral protein kinase or both

22. Foscarnet (phosphonoformate) Mechanism of action: – All polymerases need P-P as a cofactor – PFA is analog of P-P – binds to DNA polymerase -blocks P-P binding – Resistance? - altered DNA polymerase Efficacy/toxicity – active on ACV GCV resistant viruses HSV VZV and CMV – Toxic - bone, kidney, neuronal deposits Uses: – CMV retinitis and GCV r CMV in transplants – rarely used on HSV and VZV ARN cases – Rarely used on systemic HSV and VZV OH P P OH O OH O OH P CH O OH O PFA P-P